1. Field of the Invention
The present invention relates to pharmaceutical preparations for reducing the undesirable side effects, such as hot flashes and prostate enlargement, during and/or after treatment with analogs or antagonists of gonadotropin-releasing hormone (GnRHa therapy) in men as well as women. The active ingredients in these pharmaceutical preparations are characterized by estrogen action in the central nervous system. The estrogen side effects in the periphery, e.g. the prostate, the uterus or the breast glands, are reduced or completely eliminated.
2. Related Art
It is known that treatment with analogs or antagonists of gonadotropin-releasing hormone (GnRHa therapy) is an effective therapy in diseases whose intensity is influenced by the activity of the gonads.
Examples of such diseases are endometriosis, benign genital disorders, filbroid tumors of the uterus, endometrial hyperplasia, premenstrual syndrome, catamenial epilepsies, and in the broader sense all cycle-dependent disorders in women, as well as carcinoma of the prostate in men.
According to A. E. Schindler, Der Frauenarzt [The Gynecologist] 2:211-214, 1995, from 8 to 12% of women of reproductive age suffer from endometriosis.
The principal symptoms of endometriosis, along with dysmenorrhea, are dyspareunia as well as cyclical and acyclical pain in the lower abdomen. It is also associated with problems of sterility and infertility.
Now that endometriosis has been identified as a progressive estrogen-dependent disease, attempts have been made to determine, besides surgical correction, what the most effective possible hormone therapy might be. To that end, a regimen for inducing pseudo-pregnancy (W. C. Andrews and G. D. Larsen, Am. J. Obst. Gynecol. 118(5):643-651, 1974), progestational hormones (K. S. Moghissi, J. Obstet. Gynecol. 47:265-267, 1976) and later Danazol (K. W. Schweppe, Endometriose [Endometriosis] 5:4-11) have primarily been employed. Today, GNRH analogs are available for inducing a reversible, medication-induced hypoestrogenism (P. A. Regidor, et al, Zentralbl. Gynxc3xa4dkol. [Central Gynecology Newsletter] 118:283-290, 1996).
The GNRH analogs used, such as Goserelin or Leuprorelin, slow down the development of gonadotropin in the pituitary gland and thus stop estrogen production in the ovaries and lead to amenorrhea, among other effects. They must either be injected once a month or administered twice daily as a nasal spray. The side effects of the GnRH analogs are similar to the complaints that occur during menopause, such as hot flashes, sweating, headaches and depression.
Hot flashes and sweating are among the most unpleasant side effects of GnRHa therapy, which is also used in men for advanced and/or metastatic prostate cancer and thus is widely used. As a treatment that slows down hormonal action, GnRHa therapy is a palliative therapeutic principle. The quality of life of the patient during the treatment is given particular weight. According to S. Kliesch et al, Dtsch. Med. Wschr. [German Medical Weekly] 122:94-945, 1997, the incidence of hot flashes and the attendant outbreaks of sweating is a frequent and undesired accompanying symptom in up to 80% of female patients.
A comparable incidence of hot flashes in men is described as being 58% after orchiectomy and 63% in therapy with GNRH analogs (A. V. Kaisary et al, Brit. J. Urol. 67:502-508, 1991)
To prevent hot flashes in general, until the present moment, for both women and men estrogens are the means of choice. In menopause and post-menopause, they have gained wide use in therapy for menopause-related complaints.
International Patent Disclosure WO 97/21704 discloses novel compounds as GNRH antagonists, among others in combination with estrogens, including therapy for hot flashes.
In GNRH analog therapy, the use of estrogens is not advisable, because the fundamental disease being treated is an estrogen-dependent disease (G. S. Dizerga et al, Fertil. Steril. 33:649-653, 1980) and would aggravate the clinical picture is estrogens were given.
Even in men, with GnRHa therapy for carcinoma of the prostate, the conventional administration of estrogens should be considered with restraint.
The undesired side effects that occur in estrogen therapy are exhibited among other ways in metabolic effects, which for instance lead to an increase in the binding globulins for sexual steroids, thyroid hormones, and cortisone. They are expressed as breast tenderness, headache, fluid retention, nausea, weight gain, and depression (R. Jewelewicz, Fertil. Steril. 67:1-12, 1997).
In men undergoing estrogen therapy, cardiovascular complications can also be expected as an important side effect (R. Haapianen et al, Brit. J. Urol. 66:94-97, 1990; R. Stege et al, Urologie [Urology] 34:398-403, 1995). Feminizing effects are also possible (e.g. gynecomastia).
The object of the invention is to discover novel pharmaceutical preparations with high effectiveness for treating side effects, such as hot flashes, during and/or after a treatment with analogs or antagonists of gonadotropin-releasing hormone (GnRHa therapy), without the above-mentioned undesirable side effects of the xe2x80x9cclassicalxe2x80x9d estrogens occurring.
The pharmaceutical preparations according to the invention for reducing the undesirable side effects, such as hot flashes, during and/or after treatment with analogs or antagonists of gonadotropin-releasing hormone in men as well as women, contain at least one active ingredient selected from the group comprising chemically modified derivatives of 17xcex1-estradiol, chemically modified derivatives of 17xcex2-estradiol or estriol. The discovery of these novel preparations has attained the above set forth object of the invention.
Advantageous embodiments of the pharmaceutical preparations of the invention include the following particular active ingredients:
14xcex1,15xcex1-methylene-1,3,5(10),8-tetraene-3,17xcex1-diol
4-methylestra-1,3,5(10)-triene-1,17xcex1-diol
4-methylestra-1,3,5(10),6-tetraene-1,17xcex1-diol
4-methylestra-1,3,5(10),6,8-pentaene-1,17xcex1-diol ent-estradiol
4-methylestra-1,3,5(10),6-tetraene-1,17xcex2-diol
4-methylestra-1,3,5(10),6,8-pentaene-1,17xcex2-diol
17xcex1-4xe2x80x2-hydroxyphenylmethyl-4-methylestra-1,3,5(10)triene-1,17xcex2-diol
17xcex1-4xe2x80x2-hydroxyphenoxymethyl-4-methylestra-1,3,5(10)-triene-1,17xcex2-diol
17xcex1-4xe2x80x2-hydroxythiophenoxymethyl-4-methylestra-1,3,5(10)-triene-1,17xcex2-diol
17xcex1-4xe2x80x2-dimethylaminophenoxymethyl-4-methylestra-1,3,5(10)-triene-1,17xcex2-diol
17xcex1-4xe2x80x2-dimethylaminophenylmethyl-4-methylestra-1,3,5(10)-triene-1,17xcex2-diol
17xcex1-3xe2x80x2,5xe2x80x2-dimethyl-4xe2x80x2-hydroxyphenyl methyl-4-methylestra-1,3,5(10)-triene-1,17xcex2-diol
17xcex1-3xe2x80x2,5xe2x80x2-dimethyl-4xe2x80x2-hydroxyphenylmethyl-4-methylestra-1,3,5(10),6-tetraene-1,17xcex2-diol
17xcex1-4xe2x80x2-hydroxyphenoxymethyl-4-methylestra-1,3,5(10),6-tetraene-1,17xcex2-diol
14xcex2,15xcex2-methylene-8-dehydroestradiol
14xcex2,15xcex2-methylene-1,3,5(10),8-tetraene-3,17xcex1-diol
14xcex2,15xcex2-methylene-1,3,5(10),8-tetraene-3,17xcex2-diol
14xcex1,15xcex1-methylene-1,3,5(10),8-tetraene-3,17xcex2-diol
6-dehydroestriol
9(11)-dehydroestriol
The pharmaceutical preparations according to the invention include preparations for oral and parenteral administration, including topical, rectal, subcutaneous, intravenous, intramuscular, intraperitoneal, intranasal, intravaginal, intrabuccal, or sublingual administration, which along with typical vehicle and diluent agents include at least one of the active ingredients recited above or in the claims appended hereinbelow.
The forms of the administered preparations according to the invention include those given by mouth, such as tablets, capsules and lozenges or solutions; percutaneous preparations such as transdermal therapeutic systems (TTSS) or gels, sprays or salves; intranasal preparations, such as a nasal spray or nose drops; rectal preparations, such as suppositories, and parenteral preparations, such as implants, pills, and ampoules. The various embodiments of the administrated preparations are prepared with the usual solid or liquid vehicles and diluents and the typically used pharmaceutical industry adjuvants, in accordance with the desired type of administration, in suitable dosages, in the known way. The advantages of the invention are attained essentially because pharmaceutical preparations have been discovered which prevent the conventional side effects, such as hot flashes, prostate reduction and/or gynecomastia, during and/or after a treatment with analogs or antagonists of gonadotropin-releasing hormone (GnRHa therapy) both in women and in men.
The same is true for side effects in other possible hormone-suppressing therapies.